The knowledge of structure of materials at an atomic-scale level is a prerequisite to understanding material properties in general. The properties of materials are not only determined by their chemical composition, but also chemical structure of the individual molecules, as well as how these molecules are held together to form the material. Thus, even if the individual molecules of two solid materials are identical, the properties of the two materials, such as crystal lattice energies, melting points, chemical reactivity, density and solubilities, may vary widely depending on the solid-state structure of the materials, or how the molecules are arranged or packed over the longer range.
More importantly, in the area of pharmaceuticals, these differences in property may have an important impact on the performance of drugs, such as stability and bioavailability, which refers to the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For a drug that is not administered at the site of action or injected directly into the circulatory system, the bioavailability of that drug is generally determined by its solubility and its permeability through a patient's gastrointestinal membrane. A major cause of poor bioavailability of a drug is usually due to poor solubility. The spatial arrangement of the molecules affects solubility, because the crystal lattice structure (if there is any) has to be disrupted by the solvent before the drug can dissolve. For example, if the molecules of a drug are held together tightly to the crystal latter, the drug is less likely to dissolve.
Currently, most drugs are delivered in the form of crystalline powders. There is growing interest in the possibility of administering pharmaceutical drugs in non-crystalline forms, such as amorphous (a-) or nanocrystalline (n-) forms. This is attractive in cases where the crystalline forms are highly insoluble, but the a- or n-forms have greater solubility. However, the very fact that a-forms or n-forms are readily soluble also means that they are less stable. They may crystallize into the stable form during manufacturing, packaging, distribution, or storage of the drugs. Change in the solid state form may lead to unexpected changes in behavior of drugs. This change is a major concern of the pharmaceutical industry because it has considerable formulation and therapeutic implications.
Recently, a completely new avenue has been explored to administer drugs in nanocrystalline form. In this case, the structure of the solid is intermediate between a crystalline powder, where the packing of the molecules is long-range ordered, and the amorphous state, where the packing has only short-range order over a range of 10 Å or so. In this case, local packing of the molecules is quite well defined, as in the crystal, but the range of structural coherence, or order, persists only on the scale of 10's to 100's of nanometers. The nanocrystalline case presents a special appeal because the stability and solubility of the drug is expected to be intermediate between the more stable crystalline and less stable amorphous forms. This avenue should thus present the possibility of tuning stability to yield the right balance between bioavailability and shelf-life of the drug.
The non-crystalline state is also of interest as providing an alternative kinetic pathway to novel crystalline polymorphs. A dramatic recent example of this is the discovery of a previously unknown polymorph of ibuprofen, one of the most heavily studied pharmaceutical molecules, using a novel pathway that included the amorphous state.
The ability to characterize the solid-state structures of the drug is crucial to ensure the safety and therapeutic effect of the drug. The traditional method of choice for identifying (fingerprinting) polymorphs, and characterizing their structure quantitatively, is x-ray powder diffraction (XRPD). XRPD patterns are routinely placed in drug patents to uniquely identify the structural form (or forms) that will be approved for use as a commercial drug. Though single crystal studies are preferred for structure solution, quantitative analysis of XRPD patterns also can yield the atomic arrangement and molecular packing in the polymorphs (1), and is often the method of choice for refining previously solved structures using the Rietveld method (2, 3). In cases when single crystals are not available, or when studying powdered samples, such as phase analysis of a pellet, XRPD must be used and is highly successful. XRPD is therefore indispensable both in the pharmaceutical research and industrial communities.
A significant limitation of traditional crystallographic methods is that they break down on the nanoscale and are not appropriate for the characterization, or identification, of different a-phases and certain n-phases of drugs. Currently, there is no reliable experimental method for structural identification and characterization of amorphous and certain nanocrystalline pharmaceutical molecular solids. The powerful tools of crystallography begin to lose their power for structures on the nanoscale, sometimes referred to as the nanostructure problem (4). Conventional XRPD patterns become broad and featureless in these cases and are not useful for differentiating between different local molecular packing arrangements. These patterns can neither be used for identification of the structural phases present, other than a generic description that the structure is “amorphous” or “x-ray amorphous”, nor can they be used for a full quantitative structural characterization (20). It has recently been suggested that Fourier transforming the conventional XRPD data to obtain a pair distribution function (PDF) (5, 6) allows more information to be extracted (7); however, there are no clear examples where this has successfully been applied to obtain a full quantitative structural characterization. The reason is that the information content in conventional XRPD data from “x-ray amorphous” samples is very limited, and PDF, which involves Fourier transformation of the data, does not add any information, and so the information content in the PDF is similarly limited.
Thus, atomic structures of certain nanostructured materials or amorphous pharmaceutical materials are not accessible by conventional methods used on crystalline materials. Furthermore, certain crystalline pharmaceutical materials with significant nano-range structural distortions which are not reflected in the average structure cannot be studied using conventional XRPD methods either. Thus, there is an important unsolved problem in nanoscience and in pharmaceutical characterization of certain non-crystalline forms, such as n-forms and a-forms, of drugs. Accordingly, there is a great need to characterize structures of solid small organic compounds, particularly pharmaceutical compounds.